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Molecular Pathogenesis of Radiation-Induced Cell Toxicity in Stem Cells
Hur, Wonhee,Yoon, Seung Kew MDPI 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.12
<P>Radiation therapy is an effective cancer therapy, but damage to normal tissues surrounding the tumor due to radiotherapy causes severe complications. The importance of the therapeutic area between tumor suppression and normal tissue injury has long been highlighted in radiation therapy. Recent advances in stem cell biology have shown that stem cell (SC) responses to genotoxic stresses of ionizing radiation can improve the therapeutic effect of radiation by repairing damaged cells. In contrast, cancer stem cells (CSCs), a small subpopulation of cells within tumors, are generally resistant to chemotherapy and radiotherapy and cause tumor recurrence. Although the underlying mechanisms are not clearly understood in detail, efforts are still underway to identify SC treatment or CSC resistant pathogenesis of DNA damage agents such as radiation therapy. In response to radiation, CSCs differ from normal SCs in their biological properties due to severe deregulation of the self-renewal ability in CSCs. Differences of cleavage mode, cell cycle characteristics, replication potential, and activation/inactivation of DNA damage treatment and cancer-specific molecular pathways between normal SCs and CSCs confer a malignant phenotype upon CSCs. However, further studies are needed to identify normal SC and CSC-specific targets. In this review, we summarize the current advances in research regarding how normal SCs and CSCs respond to ionizing radiation, with a special emphasis on cell toxicity, radiosensitivity, signaling networks, DNA damage response (DDR) and DNA repair. In addition, we discuss strategies to develop new diagnostic and therapeutic techniques for predicting responses to cancer treatment and overcoming radiation-related toxicity.</P>
Integrative Transcriptome and Metabolome Analysis o fHepatic Cancer Stem Cells
( Wonhee Hur ),( Jae Yong Ryu ),( Hyun Uk Kim ),( Jun Ho Lee ),( Eun Byul Lee ),( Sang Yup Lee ),( Seung Kew Yoon ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1
Background: Liver cancer stem cells (LCSCs) are known to be responsible for cancer recurrence, metastasis and resistance to radiation and chemotherapy. Hence, understanding mechanisms of their resistance to several cancer treatments are critical in combating cancers. In an attempt to metabolic characterization by which CD133 expressing LCSCs mediate tumor formation and growth, metabolic pathway analysis was employed to compare metabolic changes between CD133+ and CD133-isolated from the HCC cells. Methods: CD133(+) and CD133(-) Huh-7 cell were isolated by FACS. Transcriptomic profiles of CD133-expressing LCSCs and exo-metabolic profiles of 60 cancer cell lines were integrated with a human generic metabolic model, Recon 2, to generate CD133(+)/(-) specific liver cancer metabolic models; these two models were employed to simulate their metabolic states. Results: Metabolome analyses were conducted for both CD133(+) and CD133(-) Huh-7 cells in order to directly observe global metabolic changes through quantification of intracellular metabolites in these two types of LCSCs. In this study, we show that the intracellular ATP concentration was 42% higher in the metabolic model of the CD133(+) cells, compared to the CD133(-) cells. Furthermore, we have demonstrated that the increased expression of c-Myc in the metabolic model of the CD133(+) cells induced cell proliferation, glycolysis and glutaminolysis. c-Myc expression in CD133(+) cells induced fatty acid oxidation and mitochondrial biogenesis genes. Our data suggest that c-Myc expression in CD133-expressing LCSCs regulates glucose metabolism and mitochondrial biogenesis and is an important regulator of energy metabolism in the liver cancer in response to pathologic stress. Conclusions: Integrative systems analysis involving constraint-based modeling and simulation was conducted to better understand metabolic characteristics of LCSCs and potential cues for their anticancer treatment resistances. In conclusion, the prediction results from these integrative systems metabolic analysis conducted herein will further contribute to elucidating metabolic pathway of liver cancer cell.
( Wonhee Hur ),( Sung Woo Kim ),( Young Ki Lee ),( Jung Eun Choi ),( Sung Woo Hong ),( Seung Kew Yoon ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-
Background: This study aimed to investigate the microRNA (miRNA) profile and the functions and pathways of their downstream targets in non-alcoholic fatty liver disease (NAFLD). Methods: Microarray and stem-loop reverse transcription- polymerase chain reaction were utilized to detect dysregulated miRNA in murine models of high fat diet-induced NAFLD. And then we looked for direct miRNA targets by performing pair-wise correlation coefficient analysis on expression levels of mRNAs and by comparing these results with predicted miRNA targets from TargetScan5.1. Results: HFD-feeding mice from 3 to 12 months showed hepatic steatosis and hepatic inflammation. However, there are no inflammation, steatosis, and fibrosis regions in liver from Chow group throughout entire feeding periods. Inflammatory foci were observed over 6 months after HFD indicating NASH. In cDNA microarray analysis, total 2287 genes were differentially expressed between HFD and Chow group. Among those genes, the genes related-metabolic pathway was up- regulated at 3 months while those related inflammatory response were up-regulated at late stage of over 6 months in HFD group. Furthermore, we identified 15 new miRNAs-target gene pairs by bioinformatics analysis and further confirmed their expression by stem-loop RT-PCR (miR-451, miR-494, miR-720, miR-34a, miR-1224, etc). A gene set enrichment analysis Furthermore, Gene Ontology (GO) and functional enrichment analysis on these genes demonstrated significant enrichment in biological processes related to lipid and glucose metabolism and inflammation in NAFLD. Conclusions: These results demonstrated the miRNA/mRNA profile of HFD-induced NAFLD in mice model defined a network of putative functional miRNA-target regulatory relations and the identified genes may be useful to understanding of pathogenesis in chronic liver disease and the development of target therapy for inflammation and liver fibrosis. Supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0014620).
( Wonhee Hur ),( Sung Woo Kim ),( Young Ki Lee ),( Jung Eun Choi ),( Sung Woo Hong ),( Seung Kew Yoon ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1
Background: This study aimed to investigate the microRNA (miRNA) profile and the functions and pathways of their downstream targets in non-alcoholic fatty liver disease (NAFLD). Methods: Microarray and stem-loop reverse transcriptionpolymerase chain reaction were utilized to detect dysregulated miRNA in murine models of high fat diet-induced NAFLD. And then we looked for direct miRNA targets by performing pair-wise correlation coefficient analysis on expression levels of mRNAs and by comparing these results with predicted miRNA targets from TargetScan5.1. Results: HFD-feeding mice from 3 to 12 months showed hepatic steatosis and hepatic inflammation. However, there are no inflammation, steatosis, and fibrosis regions in liver from Chow group throughout entire feeding periods. Inflammatory foci were observed over 6 months after HFD indicating NASH. In cDNA microarray analysis, total 2287 genes were differentially expressed between HFD and Chow group. Among those genes, the genes related-metabolic pathway was upregulated at 3 months while those related inflammatory response were up-regulated at late stage of over 6 months in HFD group. Furthermore, we identified 15 new miRNAs-target gene pairs by bioinformatics analysis and further confirmed their expression by stem-loop RT-PCR (miR-451, miR-494, miR-720, miR-34a, miR-1224, etc). A gene set enrichment analysis Furthermore, Gene Ontology (GO) and functional enrichment analysis on these genes demonstrated significant enrichment in biological processes related to lipid and glucose metabolism and inflammation in NAFLD. Conclusions: These results demonstrated the miRNA/mRNA profile of HFD-induced NAFLD in mice model defined a network of putative functional miRNA-target regulatory relations and the identified genes may be useful to understanding of pathogenesis in chronic liver disease and the development of target therapy for inflammation and liver fibrosis. Supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0014620).
철도차량 2 차 횡댐퍼 및 궤도특성에 따른 차체 횡변위 변화 연구
유원희(Wonhee You),신유정(Yujeong Shin),허현무(Hyunmoo Hur),박준혁(Joonhyeok Park) 한국소음진동공학회 2012 한국소음진동공학회 학술대회논문집 Vol.2012 No.4
In railway vehicle, riding comfort depends mainly on the secondary lateral damper and track condition. When the damping force of lateral damper becomes abnormal condition or the track condition is worse, the running stability and ride comfort of the railway vehicles go down. In addition, the lateral motion of carbody is increased. Therefore, the lateral motion of carbody is reviewed carefully by considering lateral damping force and track condition of the railway line in design stage. In this study, the lateral displacement of carbody was studied in accordance with lateral damping force and track condition. The target vehicle is EMU for subway line.
유원희(Wonhee You),신유정(Yujeong Shin),허현무(Hyunmoo Hur),박준혁(Junhyuk Park) 한국소음진동공학회 2013 한국소음진동공학회 학술대회논문집 Vol.2013 No.4
The maximum speed is one of the most important performance in high speed railway vehicle. The higher the train speed is, the worse the ride comfort is. In order to solve this problem, a semi-active or active suspension can be applied to high speed railway vehicle. The variable damper with hydraulic solenoid valve is used in the semi-active suspension. But the variable damper with hydraulic solenoid valve requires tank for supplying fluid. The MR(Magneto Rheological) damper can be considered instead of hydraulic variable damper which needs additional device, I.e. reserver tank for fluid. In the case of active suspension, hydraulic actuator or electro-mechanical one is used to suppress the carbody vibration in railway vehicle. In this study the MR damper and electro-mechanical actuator was considered in secondary suspension system of high speed railway vehicle. The dynamic analysis was performed by using 10-DOF dynamic equations of railway vehicle. The performance of the semi-active suspension and active suspension system were reviewed by using MATLAB/Simulink S/W. The vibration suppression effect of semi-active and active suspension system were investigated experimentally by using 1/5-scaled railway vehicle model.